Existing standards, reporting guidelines, and practical considerations
Standards of adaptive trial designs
Prospective specification of adaptations and analysis
- We need statistical analysis plan with pre-specified models for interim monitoring and final analysis, priors, and assumptions
Evaluation of statistical (operating) characteristics
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We need to characterize the statistical (operating) characteristics such as type I error rate, power, and expected sample size
- We often need to submit our adaptive trial designs plans to the FDA or other regulatory agencies
Beneficial to use simulations to evaluate characteristics beyond the statistical characteristics mentioned above. For instance, sometimes simulations can be used for resource planning in terms of drug supplies and etc.
Standards of adaptive trial designs - continued.
Communication and vetting of trial design with key stakeholders
Key stakeholders may include clinical investigators, institutional review boards, data safety monitoring boards, patient representatives and groups, potential participants, funders, and regulatory agencies
Important that key stakeholders understand proposed design
Standards of adaptive trial designs - continued.
Ensure clinical trial infrastructure is adequate to support planned adaptation(s)
- Demonstrate that the infrastructure can allow for timely electronic data capture, medical monitoring, and data transfers, and is able to implement adaptations in a timely manner
Standards of adaptive trial designs - continued.
Consider sources of operational bias and implement ways to minimize
Operational bias occurs when information about the ongoing trial causes changes to the participant pool, investigator behavior, or other aspects that affect the the conduct of the trial
Ensure proper oversight of the trial by the Data Monitoring Committee (DMC)
Proactivity of data monitoring committee
The FDA Adaptive Design Guidance:
- “Because the DMC is unblinded to interim study results it can help implement the adaptation decision according to the prospective adaptation algorithm, but it should not be in a position to otherwise change the study design except for serious safety-related concerns that are the usual responsibility of a DMC”
Standards of adaptive trial designs - continued.
The reporting of adaptive trials should be consistent with the CONSORT statement
- In 2020, Dimairo and colleagues published their CONSORT extension to adaptive designs
Reporting guidelines
Several good examples of how to report adaptive clinical trials in this manuscript
Practical considerations
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Planning adaptive trial designs require resources and time
- Best to plan ahead with key stakeholders with statistical, content, and operational expertise to make the trial possible
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Customized education and training plans will likely be required for the vendors, investigators, and other personnel involved in the trial
- Critical thinking is needed from the personnel involved to create flexible technology systems and procedures required to execute these clinical trials
During the conduct, it is important to document what happened, maintain proper firewall and manage external communications effectively
Practical considerations - continued.
Regardless of the trial design, the successful conduct of any clinical trial requires cross-functional coordination and cooperation
Successful implementation of complex trial designs likely require much more coordination and cooperation
Having a strong, diverse, and collaborative team is an asset
It might be important to honestly ask and be upfront, if we have the relevant expertise available to design and execute the trial